Intravenous injection of leconotide, an omega conotoxin: synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain.
Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312-5.0 mg/kg intraperitoneal) and leconotide (0.002-200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED(50) = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED(50) = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED(50) = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED(50) = 1.24 ± 1.30 mg/kg). Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.


Large root systems: are they useful in adapting wheat to dry environments?
There is little consensus on whether having a large root system is the best strategy in adapting wheat (Triticum aestivum L.) to water-limited environments. We explore the reasons for the lack of consensus and aim to answer the question of whether a large root system is useful in adapting wheat to dry environments. We used unpublished data from glasshouse and field experiments examining the relationship between root system size and their functional implication for water capture. Individual root traits for water uptake do not describe a root system as being large or small. However, the recent invigoration of the root system in wheat by indirect selection for increased leaf vigour has enlarged the root system through increases in root biomass and length and root length density. This large root system contributes to increasing the capture of water and nitrogen early in the season, and facilitates the capture of additional water for grain filling. The usefulness of a vigorous root system in increasing wheat yields under water-limited conditions maybe greater in environments where crops rely largely on seasonal rainfall, such as the Mediterranean-type environments. In environments where crops are reliant on stored soil water, a vigorous root system increases the risk of depleting soil water before completion of grain filling.


Ratio of End-Systolic Volume to Left Atrial Area Is a Solid Benchmark of Systolic Dysfunction in Non-Ischemic Cardiomyopathies.
BACKGROUND Impairment of systolic function and late gadolinium enhancement (LGE) are well-known negative prognostic markers in non-ischemic cardiomyopathies (NICMPs). There is limited knowledge of the geometrical rearrangements of the ventricle volumes over size of the left atrium and their connections with systolic dysfunction and existence of LGE. MATERIAL AND METHODS Consecutive cases of NICMPs with impaired systolic function and controls were included from a computerized database of cardiac magnetic resonance exams for a 2.5-year period. Ratios made from volumetric parameters over left atrial area (LAA) area were calculated. RESULTS Our study included 205 cases referred to cardiac magnetic resonance (CMR); age was 48.7±17.0 years (range 15.2-80.4), male-to-female ratio 137 (66.8%): 68 (33.2%), (both p>0.05). LGE was significantly correlated with impairment of systolic function (Rho CC=0.395; p<0.001). For detection of systolic impairment, a critical value of end-systolic-volume (ESV)/LAA of ≥2.7 had an area under curve (AUC) of 0.902 (0.853-0.939), p<0.001; stroke-volume (SV)/LAA ≤3.0 had AUC=0.782(0.719-0.837), p<0.001, and end-diastolic volume (EDV)/LAA <7.4 had an AUC of 0.671 (0.602-0.735); p<0.001. In analyses of LGE, a value of SV/LAA of ≤3.0 had an AUC of 0.681 (0.612-0.744), p<0.001; while ESV/LAA and EDV/LAA were not significant (both p<0.05). ESV/LAA was correlated with systolic dysfunction (Rho-correlation-coefficient: 0.688; p<0.001) and existence of linear midventricular LGE stripe (Rho-CC=0.446; p<0.001). CONCLUSIONS ESV/LAA was the most effective for detection of systolic impairment and was associated with the existence of LGE. Prospective validation for clinical applicability and prognostic relations are warranted in future studies.


Investigation of Hydrogel Isolated from Seeds of Ocimum basilicum as Binder.
Ayurvedic powders are widely used as therapeutic agents but most of them have unpleasant taste and large doses. One of the possible approach to overcome these drawbacks is to represent them in unit dosage form i.e. tablet dosage form. The purpose of this study is to elucidate and quantify the compressibility and compactibility of herbal granules prepared by using hydrogel isolated from whole seeds of Ocimum basilicum as a novel binder. The compressibility is the ability of the powder to deform under pressure and the compactibility is the ability of a powder to form coherent compacts. To test the functionality of novel excipients, Sonnergaard proved a simple linear model to confirm compactability, which is an uncomplicated tool for quantification. The tablets were compressed at increasing compression pressures and were evaluated for various mechanical properties. The linear relationship between specific crushing strength and compression pressure revealed the compactibility of the herbal granules and the linear relationship between porosity and logarithm of compression pressure revealed the compressible nature of the herbal granules according to the model developed by Sonnergaard. Thus the hydrogel isolated from whole seeds of Ocimum basillicum had potential as a granulating and binding agent.


Identification of the site of Epstein-Barr virus persistence in vivo as a resting B cell.
Epstein-Barr (EBV) is a powerful immortalizing virus for human B lymphocytes in vitro and is associated with several human neoplasias in vivo. Previously, we have shown that the majority of EBV-infected cells in the peripheral blood of healthy, persistently infected individuals do not express the activated phenotype, e.g., high levels of cell surface CD23 and CD80 (B7), characteristically expressed on in vitro-immortalized cells. Here, we show that > or = 90% of the CD23-, virus-infected cells in the peripheral blood are in G0 and therefore resting. The remaining cells may be G1 arrested, but we were unable to detect a significant number of cells traversing the S-G2-M stages of the cell cycle. The mRNA for LMP2A, but not EBNA1 originating from Qp, was readily detected in this population, and these cells appear competent in the processing and presentation of antigen by class I major histocompatibility complex. We propose that these resting B cells are the site of long-term latent persistence for EBV. We further propose that the persistence of the virus in a resting B7- B cell provides an important mechanism to escape immunosurveillance. The demonstration that EBV can persist latently in a resting B cell means that the immortalizing functions of EBV can be down regulated in a normal B cell. This conclusion has important implications for understanding and controlling EBV-associated neoplasia.


XUV coherent diffraction imaging in reflection geometry with low numerical aperture.
We present an experimental realization of coherent diffraction imaging in reflection geometry illuminating the sample with a laser driven high harmonic generation (HHG) based XUV source. After recording the diffraction pattern in reflection geometry, the data must be corrected before the image can be reconstructed with a hybrid-input-output (HIO) algorithm. In this paper we present a detailed investigation of sources of spoiling the reconstructed image due to the nonlinear momentum transfer, errors in estimating the angle of incidence on the sample, and distortions by placing the image off center in the computation grid. Finally we provide guidelines for the necessary parameters to realize a satisfactory reconstruction within a spatial resolution in the range of one micron for an imaging scheme with a numerical aperture NA < 0.03.


Wireworm (Coleoptera: Elateridae) intoxication symptoms indicate the postharvest presence of broflanilide residues in soil collected from potato fields.
Wireworms are primary pests of potatoes in Canada with relatively few effective control options. Recently, a new meta-diamide insecticide, broflanilide, was registered in Canada and the United States as an in-furrow spray applied at planting that provides protection of tubers from feeding damage and dramatically reduces wireworm populations. As part of our routine screening of wireworm response to novel insecticides, we exposed wireworms (predominantly Agriotes obscurus; N=2320) to field soil collected from plots to which either bifenthrin (Capture 2EC) or broflanilide (Cimegra) had been applied at registered rates 124-145 and 314-335 days previously in 2018, 2019, and 2021. Wireworm behavioral responses were assessed using a previously developed numerical scale, and indicated residues were present in sufficient quantity in all broflanilide and most bifenthrin-treated plots to induce morbidity. Transfer of affected wireworms to untreated soil indicated morbidity was generally reversible after exposure to bifenthrin, but not after exposure to broflanilide. There was an inverse relation between wireworm size and the degree of morbidity induced by exposure to broflanilide, but not bifenthrin. Analyses of soil residues indicated readily quantifiable levels of broflanilide still present in undisturbed (not harvested) field soil 314-335 days after application. Insecticide residues in soil samples from disturbed (harvested) sections of the potato plots were lower, as was the degree of morbidity of wireworms exposed to this soil. The use of wireworms as bioindicators of insecticide residues, and the implications of insecticide persistence for wireworm management are discussed.


Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds.
Canine diabetes mellitus (DM) is a common endocrine disease in domestic dogs. A number of pathological mechanisms are thought to contribute to the aetiopathogenesis of relative or absolute insulin deficiency, including immune-mediated destruction of pancreatic beta cells. DM risk varies considerably between different dog breeds, suggesting that genetic factors are involved and contribute susceptibility or protection. Associations of particular dog leucocyte antigen (DLA) class II haplotypes with DM have been identified, but investigations to date have only considered all breeds pooled together. The aim of this study was to analyse an expanded data set so as to identify breed-specific diabetes-associated DLA haplotypes. The 12 most highly represented breeds in the UK Canine Diabetes Register were selected for study. DLA-typing data from 646 diabetic dogs and 912 breed-matched non-diabetic controls were analysed to enable breed-specific analysis of the DLA. Dogs were genotyped for allelic variation at DLA-DRB1, -DQA1, -DQB1 loci using DNA sequence-based typing. Genotypes from all three loci were combined to reveal three-locus DLA class II haplotypes, which were evaluated for statistical associations with DM. This was performed for each breed individually and for all breeds pooled together. Five dog breeds were identified as having one or more DLA haplotype associated with DM susceptibility or protection. Four DM-associated haplotypes were identified in the Cocker Spaniel breed, of which one haplotype was shared with Border Terriers. In the three breeds known to be at highest risk of DM included in the study (Samoyed, Tibetan Terrier and Cairn Terrier), no DLA haplotypes were found to be associated with DM. Novel DLA associations with DM in specific dog breeds provide further evidence that immune response genes contribute susceptibility to this disease in some cases. It is also apparent that DLA may not be contributing obvious or strong risk for DM in some breeds, including the seven breeds analysed for which no associations were identified.


Unified basis for the respirometric evaluation of inhibition for activated sludge.
This paper explores the merit of the oxygen uptake rate (OUR) profile obtained by means of respirometry as the basic mechanistic instrument for evaluating activated sludge inhibition. Experimental OUR data are generated using the synthetic peptone-based substrate and inhibition is tested with 60 mg/L hexavalent chromium and 33 mg/L nickel additions, corresponding to EC50 levels determined using the standard ISO 8192 procedure. Experimental results are evaluated by model calibration using ASM1 modified for dual hydrolysis and ASM3 modified for simultaneous growth. Model evaluations indicate that inhibition affects not only growth, but also other significant microbial mechanisms such as substrate storage and hydrolysis, leading to conclude that the proposed approach will enable to visualize the overall impact of the inhibitory compound on every stage of substrate biodegradation, through inspection and evaluation of the entire OUR profile.


Factors affecting erectile function after radical prostatectomy.
Radical retropubic prostatectomy is a therapeutic option for treatment of localized prostate cancer. The goal of radical prostatectomy is to completely remove the tumor while preserving erectile function and urinary continence as well as factors that determine the postoperative quality of life. There are many factors influencing sexual function after radical prostatectomy of localized prostate cancer. All factors can be divided into the preoperative, postoperative and intraoperative. In this paper we examine the significance of individual factors affecting erectile dysfunction following surgical treatment. The study included 36 patients who underwent nerve sparing radical prostatectomy at the Urology Clinic, Clinical Center of Sarajevo University in period from January 2009 until December 2010. Out of 84 patients tested, radical retropubic prostatectomy with the reservation of neurovascular bundles was performed in 36 patients (42.8%). Of this number, both of the neurovascular bundles were preserved in 28 patients (77.7%) and one in 8 patients (22.2%). The positive predictive factor for erectile function after radical retropubic prostatectomy is the preoperative sexual function, younger age, preservation of both neurovascular bundles and early rehabilitation therapy.


Primary cutaneous B-cell lymphoma: review and current concepts.
Primary cutaneous B-cell lymphoma (PCBCL) has only recently been recognized as a distinct clinical entity. With the advent of improved immunophenotyping and immunogenotyping, increasing numbers of PCBCL cases are being diagnosed. However, there is much confusion regarding the classification, treatment, and prognosis of these patients. The purpose of this article is to review and analyze the available data to provide the clinician with a concise summary of the diagnosis, prognosis, and treatment of PCBCL. We conducted a thorough review of the medical literature on PCBCL, with a focus on classification, prognosis, and treatment trials. PCBCL is defined as a B-cell lymphoma originating in the skin. There is no evidence of extracutaneous disease at presentation and for 6 months after diagnosis, as assessed by adequate staging procedures. Currently, the European Organization for Research and Treatment of Cancer classification is the most concise disease classification scheme, dividing the subtypes of PCBCL by clinical behavior and histopathologic findings. Based on this classification, the most common subtype of PCBCL is follicular center cell lymphoma. PCBCL is generally an indolent form of lymphoma with a good prognosis. Although local cutaneous recurrences are observed in 25% to 68% of patients, dissemination to internal organs is rare. Five-year survival rates typically range from 89% to 96%. A specific subtype, large B-cell lymphoma of the leg, is noted to have a poorer prognosis, with a 5-year survival rate of 58%. Overly aggressive treatment of PCBCL has not been shown to improve survival or prevent relapse. The treatment of choice usually varies depending on the type of PCBCL, the body surface area, and the location of the involvement, as well as the age and general health condition of the patient. The majority of studies indicate that PCBCL is highly responsive to radiation therapy. Polychemotherapy should be reserved for involvement of noncontiguous anatomic sites or those with extracutaneous spread.


Assessment of the requirements for magnesium transporters in Bacillus subtilis.
Magnesium is the most abundant divalent metal in cells and is required for many structural and enzymatic functions. For bacteria, at least three families of proteins function as magnesium transporters. In recent years, it has been shown that a subset of these transport proteins is regulated by magnesium-responsive genetic control elements. In this study, we investigated the cellular requirements for magnesium homeostasis in the model microorganism Bacillus subtilis. Putative magnesium transporter genes were mutationally disrupted, singly and in combination, in order to assess their general importance. Mutation of only one of these genes resulted in strong dependency on supplemental extracellular magnesium. Notably, this transporter gene, mgtE, is known to be under magnesium-responsive genetic regulatory control. This suggests that the identification of magnesium-responsive genetic mechanisms may generally denote primary transport proteins for bacteria. To investigate whether B. subtilis encodes yet additional classes of transport mechanisms, suppressor strains that permitted the growth of a transporter-defective mutant were identified. Several of these strains were sequenced to determine the genetic basis of the suppressor phenotypes. None of these mutations occurred in transport protein homologues; instead, they affected housekeeping functions, such as signal recognition particle components and ATP synthase machinery. From these aggregate data, we speculate that the mgtE protein provides the primary route of magnesium import in B. subtilis and that the other putative transport proteins are likely to be utilized for more-specialized growth conditions.


[Furosemide-sensitive transport of chloride through the apical membrane of cells of the proximal tubule of the triton kidney].
The effect of furosemide on transtubular electrical potential (Vt) as well as on the potentials of apical (Va) and basolateral (Vb) membranes of the Triturus vulgaris proximal nephron cells was studied in alteration of the electrochemical potential gradient Na+ and Cl- through the apical membrane. Furosemide did not change the Va and Vb provided the concentration of NaCl in the lumen of proximal canal was the same as in the blood plasma. When the NaCl concentration diminished in the lumen furosemide increased Va and Vb, the Vt remaining unchanged. The effect of furosemide is considerably lesser when the Cl- concentration alone diminishes in the lumen. The data obtained suggest presence of furosemide-sensitive transport of Cl- in the apical membrane of proximal canal cells in the Triturus kidney. This membrane seems to have systems of electrogenic transport of Cl- insensitive to furosemide but depending on the Na+ electrochemical potential gradient.


The effect of a body shape index (ABSI) and its interaction with low estimated glomerular filtration rate (eGFR) on osteoporosis in elderly Chinese.
Both obesity and chronic kidney disease (CKD) contribute to osteoporosis risk, but the effect of a newly developed index (e.g., a body shape index, ABSI) of central obesity and its interaction with low estimated glomerular filtration rate (eGFR) on osteoporosis remains unknown. A total of 2534 Chinese individuals were enrolled in our ongoing cohort study: Osteoporosis Preventive Project. ABSI and eGFR were calculated as obesity-related indexes and renal function markers, respectively. A logistic regression model was used to estimate the association between osteoporosis and related clinical parameters (e.g., ABSI, eGFR), and to assess the additive and multiplicative interactions between risk factors and osteoporosis. Relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (SI) were calculated to assess the additive interaction. High ABSI was significantly associated with an increased risk of osteoporosis in participants compared with the lowest quartile of ABSI in both crude and adjusted models. Individuals in the lower quartiles of eGFR had a significantly increased risk of osteoporosis compared with those in the highest quartiles in crude models. After adding age and other variables in the model, the association was abolished. In addition, after adjusting for variables, high ABSI with low eGFR (RERI: 0.45, 95% CI: 0.15-0.75; AP: 0.39, 95% CI: 0.17-0.60) still displayed a noticeable interaction on the risk of osteoporosis. The multiplicative interactive effect between high ABSI with low eGFR on osteoporosis was statistically significant in the multivariable-adjusted model (P < 0.05). Our study indicated that higher ABSI increases the risk of osteoporosis independently and synergistically with low eGFR in Chinese elderly adults. The findings increase our understanding of the interactions of osteoporosis risk factors and may help provide potential interventions for osteoporosis.


Postoperative Corneal Injuries: Incidence and Risk Factors.
Previous studies of postoperative corneal injury rates relied on provider-initiated incident reports, which may underestimate the true incidence. Postoperative administration of proparacaine eye drops is used almost exclusively to diagnose corneal injury; therefore, identifying instances of administration may provide a better estimate of corneal injuries. We compared proparacaine administration versus provider-initiated reports to determine rates of corneal injury. In addition, potential associations between clinical variables and injury were assessed with a matched case-control study. The health records of 132,511 sequential adult postanesthesia recovery room admissions (January 1, 2011 to June 30, 2017) were reviewed to identify postoperative proparacaine administration and incident reports of corneal injury. Patients with corneal injury were matched with control patients at a 1:2 ratio to assess factors associated with injury. Proparacaine drops were administered to 442 patients (425 patients received proparacaine for diagnosis and 17 patients received proparacaine for unrelated reasons). Incident reports identified 320 injuries, and the aggregate corneal injury count was 436 (incidence, 3.3 injuries [95% confidence interval {CI}, 3.0-3.6] per 1000 cases of general anesthesia). Proparacaine administration had a greater case ascertainment percentage than incident reporting (97.5% vs 73.4%; P < .001). The matched case-control analysis found greater risks associated with longer duration of anesthesia (odds ratio, 1.05 [95% CI, 1.03-1.07] per 10 minutes of anesthesia; P < .001) and nonsupine surgical position (odds ratio, 3.89 [95% CI, 2.17-6.98]; P < .001). Patients with injuries also had more evidence of sedation and agitation during anesthesia recovery. Calculation of incidence by using the administration of a medication (proparacaine eye drops) that is almost exclusively used to diagnose a specific injury (corneal injury) showed higher case ascertainment percentage than incident-reporting methods. Similar strategies could be used to monitor the rates of other adverse events.


Evaluation of the effect of storage at -70 degrees C for six months on hemostatic function testing in dogs.
Freezing is a routine method of storage for plasma that is to be used in evaluating certain aspects of hemostatic function in many species. The purpose of this study was to evaluate the effect of storage at -70 degrees C for 6 mo on canine plasma samples. On fresh and frozen plasma from 12 clinically healthy dogs, prothrombin time, activated partial thromboplastin time, thrombin clotting time, fibrinogen determination, antithrombin III activity, fragment D and E assay, and protamine sulfate test were performed. Clinical agreement analysis was utilized to determine the effect of such storage on all assays. Individual differences detected between fresh and frozen samples were all within 2 standard deviations of the mean difference. With the exception of the activated partial thromboplastin time, storing canine plasma at -70 degrees C for 6 mo has no significant effect on hemostatic function, as assessed by these tests.


Effect of rearing system (free-range vs. cage) on gut and muscle histomorphology and microbial loads of Italian White breed rabbits.
The growing consumers' interest on animal welfare has raised the request of products obtained by alternative rearing systems. The present study was conducted to assess the influence of housing system on gut and muscle morphology and on microbial load in rabbits reared under free-range (FR) and cage system (CS). A total of forty weaned (35 days of age) male Italian White breed rabbits were allotted according to the rearing system, and at 91 days of age were randomly selected and slaughtered for the morphological evaluation of tissue from duodenum and longissimus lumborum. Morphometric analysis of the villus height, villus width, crypt depth, villus height/crypt depth ratio, and villus surface was performed. The microbial loads on hind muscle was determined by total mesophilic aerobic count (TMAC), E. coli and Enterobacteriaceae; whereas, total anaerobic bacteria count (TABC) and total mesophilic aerobic count (TMAC), E. coli and Enterobacteriaceae was determined on caecal content. Rearing system did not interfere with the duodenum and muscle histomorphology in both rabbit groups. Similarly, microbial load of caecal content showed no significant differences on the TABC and TMAC. Conversely, significant difference was found for E. coli strains in caecal content, with the lower counts in free-range compared to caged rabbits (P< 0.01). Microbiological assay of muscle revealed significant lower TMAC in FR vs. CS rabbits (P< 0.05). All rabbit meat samples were negative for E. Coli and Enterobacteriaceae. Free-range could be considered a possible alternative and sustainable rearing system in rabbits to preserve gut environment and muscle quality.


Newly identified Chinese hamster ovary cell mutants defective in peroxisome biogenesis represent two novel complementation groups in mammals.
We isolated peroxisome biogenesis mutants from Chinese hamster ovary (CHO) cells, using the 9-(1'-pyrene)nonanol/ultraviolet (P9OH/ UV) method and wild-type CHO-K1 cells that had been stably transfected with cDNA encoding Pex2p (formerly peroxisome assembly factor-1, PAF-1). Three mutant cell clones, ZP110, ZP111, and ZP114, showed cytosolic localization of catalase, thereby indicating a defect in peroxisome biogenesis, whereas ZP112 and ZP113 contained fewer but larger catalase-positive particles. Mutant ZP115 displayed an aberrant, tubular structure immunoreactive to anti-catalase antibody. Mutants lacking morphologically recognizable peroxisomes also showed the typical peroxisome assembly-defective phenotype such as severe loss of catalase latency and resistance to 12-(1'-pyrene)dodecanoic acid (P12)/UV treatment. ZP110 and ZP111, and ZP114 were found to belong to two novel complementation groups, respectively, by complementation group analysis with cDNA transfection and cell fusion. Cell fusion with fibroblasts from patients with peroxisome biogenesis disorders such as Zellweger syndrome revealed that ZP110 and ZP114 could not be classified to any of human complementation groups. Thus, ZP110/ZP111 and ZP114 are the first, two peroxisome-deficient cell mutants of newly identified complementation groups distinct from the ten mammalian groups previously characterized.


Origin and evolution of primate social organisation: a reconstruction.
The evolution and origin of primate social organisation has attracted the attention of many researchers, and a solitary pattern, believed to be present in most nocturnal prosimians, has been generally considered as the most primitive system. Nocturnal prosimians are in fact mostly seen alone during their nightly activities and therefore termed 'solitary foragers', but that does not mean that they are not social. Moreover, designating their social organisation as 'solitary', implies that their way of life is uniform in all species. It has, however, emerged over the last decades that all of them exhibit not only some kind of social network but also that those networks differ among species. There is a need to classify these social networks in the same manner as with group-living (gregarious) animals if we wish to link up the different forms of primate social organisation with ecological, morphological or phylogenetic variables. In this review, we establish a basic classification based on spatial relations and sociality in order to describe and cope properly with the social organisation patterns of the different species of nocturnal prosimians and other mammals that do not forage in cohesive groups. In attempting to trace the ancestral pattern of primate social organisation, the Malagasy mouse and dwarf lemurs and the Afro-Asian bushbabies and lorises are of special interest because they are thought to approach the ancestral conditions most closely. These species have generally been believed to exhibit a dispersed harem system as their pattern of social organisation ('dispersed' means that individuals forage solitarily but exhibit a social network). Therefore, the ancestral pattern of primate social organisation was inferred to be a dispersed harem. In fact, new field data on cheirogaleids combined with a review of patterns of social organisation in strepsirhines (lemurs, bushbabies and lorises) revealed that they exhibit either dispersed multi-male systems or dispersed monogamy rather than a dispersed harem system. Therefore, the concept of a dispersed harem system as the ancestral condition of primate social organisation can no longer be supported. In combination with data on social organisation patterns in 'primitive' placentals and marsupials, and in monotremes, it is in fact most probable that promiscuity is the ancestral pattern for mammalian social organisation. Subsequently, a dispersed multi-male system derived from promiscuity should be regarded as the ancestral condition for primates. We further suggest that the gregarious patterns of social organisation in Aotus and Avahi, and the dispersed form in Tarsius evolved from the gregarious patterns of diurnal primates rather than from the dispersed nocturnal type. It is consequently proposed that, in addition to Aotus and Tarsius, Avahi is also secondarily nocturnal.


Reward-based decision making in pathological gambling: the roles of risk and delay.
Pathological gambling (PG) is a non-substance based addiction that shares many behavioral and neural features with substance based addictions. However, in PG behavioral and neural changes are unlikely to be confounded by effects of acute or chronic drug exposure. Changes in reward based decision-making in particular increases in impulsivity are hallmark features of addictions. Here we review studies in PG that applied three reward-related decision tasks: the Iowa Gambling Task, probability discounting and delay discounting. We discuss the findings and focus on the impact of addiction severity and the relation of effects to impulsivity measures. While there is evidence that PGs differ from healthy controls on all three tasks, there is only little support for a further modulation of impairments by addiction severity. Conceptually, delay discounting is related to impulsivity measures and findings in this task show a considerable correlation with e.g. questionnaire-based measures of impulsivity. Taken together, impairments in PG on these three tasks are relatively well replicated, although impairments appear to be largely uncorrelated between tasks. An important next step will be to conceptualize a process-based account of behavioral impairments in PG.


Neurobehavioral evaluation in the preterm and term infant.
Neurobehavioral examinations of babies, both term and preterm, have been used in neonatology for many decades. However, with the advent of new technologies and, perhaps more "scientific" ways of assessing high risk infants, it seems that neurobehavioral examinations may have become somewhat redundant in some nurseries. Yet these examinations remain an important part of clinical practice. They help to increase our understanding of an infant's behavior, including their strengths and vulnerabilities, thus enabling us to adjust our care and parent education accordingly. These examinations also assist us to identify those most at risk of developmental disabilities, enabling further assessment and intervention to be considered as early as possible. Whilst it remains a challenge to try and quantify neonatal neurobehavior, there are numerous tools available that can greatly assist us. This review did not find a tool that served all populations and all assessment purposes. Consequently, the clinician or researcher needs to choose the appropriate assessment depending on matters such as the infant's gestation and the assessment's goal and training requirements. Further research is needed to develop neurobehavioral assessment tools, particularly for extremely preterm infants, which are easily accessible in the clinical setting and can be used from birth.


Statistical analysis of minimum cost path based structural brain connectivity.
Diffusion MRI can be used to study the structural connectivity within the brain. Brain connectivity is often represented by a binary network whose topology can be studied using graph theory. We present a framework for the construction of weighted structural brain networks, containing information about connectivity, which can be effectively analyzed using statistical methods. Network nodes are defined by segmentation of subcortical structures and by cortical parcellation. Connectivity is established using a minimum cost path (mcp) method with an anisotropic local cost function based directly on diffusion weighted images. We refer to this framework as Statistical Analysis of Minimum cost path based Structural Connectivity (SAMSCo) and the weighted structural connectivity networks as mcp-networks. In a proof of principle study we investigated the information contained in mcp-networks by predicting subject age based on the mcp-networks of a group of 974 middle-aged and elderly subjects. Using SAMSCo, age was predicted with an average error of 3.7 years. This was significantly better than predictions based on fractional anisotropy or mean diffusivity averaged over the whole white matter or over the corpus callosum, which showed average prediction errors of at least 4.8 years. Additionally, we classified subjects, based on the mcp-networks, into groups with low and high white matter lesion load, while correcting for age, sex and white matter atrophy. The SAMSCo classification outperformed the classification based on the diffusion measures with a classification accuracy of 76.0% versus 63.2%. We also performed a classification in groups with mild and severe atrophy, correcting for age, sex and white matter lesion load. In this case, mcp-networks and diffusion measures yielded similar classification accuracies of 68.3% and 67.8% respectively. The SAMSCo prediction and classification experiments indicate that the mcp-networks contain information regarding age, white matter lesion load and white matter atrophy, and that in case of age and white matter lesion load the mcp-network based models outperformed the predictions based on diffusion measures.


Enhanced organic degradation and biogas production of domestic wastewater at psychrophilic temperature through submerged granular anaerobic membrane bioreactor for energy-positive treatment.
This study deals with the conversion of organic matter into methane at ambient temperature, during anaerobic digestion of domestic wastewater combined with a submerged ultrafiltration membrane with no gas-sparging. A one-stage submerged granular anaerobic membrane bioreactor (G-AnMBR) and a control anaerobic digester (UASB type) were operated during four months, after 500 days of biomass acclimatization to psychrophilic and low loading rate conditions. Membrane barrier led to the retention of biomass, suspended solids and dissolved and colloidal organic matter which greatly enhanced total COD (tCOD) removal (92.3%) and COD to methane conversion (84.7% of tCOD converted into dissolved and gaseous CH4). G-AnMBR overcame the usual long start-up period and led to a higher sludge heterogeneity, without altering the granular biomass activity. The feasibility of the G-AnMBR without gas-sparging was also assessed and the net positive energy balance was estimated around + 0.58 kWh.m-3.


The efficacy and safety of the Timothy grass allergy sublingual immunotherapy tablet in Canadian adults and children.
The effect of sublingual Timothy grass immunotherapy tablet 2800 BAU (grass SLIT-T) has been evaluated in three North American trials in adults and children who have allergic rhinitis with or without conjunctivitis (AR/C). This paper examines the effects of grass SLIT-T in Canadians. Data for grass-allergic Canadians in three randomized, placebo-controlled, double-blind trials were analyzed post hoc: 1) adults ≥18 y, grass-pollen season [GPS] 2009; 2) children 5- <18 y, 2009; and 3) adults 18-65 y and children 5- <18 y, GPS 2012. Data from the GPS 2009 trials were pooled to provide a more precise estimate of treatment effects than the individual studies would provide. In every trial, participants received once-daily grass SLIT-T or placebo approximately 12 weeks before and continuing throughout the GPS. Participants used daily electronic diaries to record AR/C symptoms and medication use for treatment of symptoms. The therapeutic effect of grass SLIT-T was measured as a total combined score (TCS = daily symptom score + daily medication score) averaged over the entire GPS. Safety was assessed by monitoring adverse events (AEs). In the three trials, 386 Canadian participants were randomized; the overall population had 2284 participants. Canadian participants treated with grass SLIT-T in the pooled adult-pediatric 2009 trials showed a 38% mean TCS reduction relative to placebo (-2.06 difference [95% CI: -3.72, -0.39]; 3.32 vs. 5.37). Participants treated with grass SLIT-T in the adult-pediatric 2012 trial showed a 37% median TCS reduction relative to placebo (-1.53 difference [95% CI: -2.1, -0.3]; 2.58 vs. 4.11). Similar efficacy findings were observed over the peak GPS. Approximately 90% of treatment-related AEs were mild or moderate in severity. Two Canadian participants had moderate systemic allergic reactions (skin, respiratory, abdominal symptoms) to grass SLIT-T; symptoms resolved within 1 hour without medical intervention or treatment. No serious or life-threatening treatment-related AEs occurred. The 2800 BAU Timothy grass SLIT-T significantly improved AR/C induced by Timothy grass pollen in adults and children ≥5 y in Canadians, which was consistent with the robust efficacy observed in the overall trial population. The treatment was generally well tolerated. Clinicaltrials.gov identifiers NCT00562159, NCT00550550, NCT01385371.


Tadalafil once daily improves ejaculatory function, erectile function, and sexual satisfaction in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia and erectile dysfunction: results from a randomized, placebo- and tamsulosin-controlled, 12-week double-blind study.
Tadalafil, a long-acting phosphodiesterase type 5 inhibitor, is approved for treating signs and symptoms of benign prostatic hyperplasia (BPH) and erectile dysfunction (ED); tamsulosin, an alpha-blocker, is approved for treating signs and symptoms of BPH. To determine the effects of tadalafil or tamsulosin on sexual function, including ejaculation and orgasm, satisfaction, and erectile function, in sexually active men with ED and lower urinary tract symptoms suggestive of BPH (LUTS/BPH). A randomized, double-blind, placebo-controlled study of tadalafil 5 mg once daily for 12 weeks in men with LUTS/BPH; tamsulosin 0.4 mg once daily was an active control. The International Index of Erectile Function (IIEF) questionnaire was administered at baseline and 4, 8, and 12 weeks. Analysis of orgasm and ejaculation was post hoc based on the IIEF-Orgasmic Function (OF) domain (IIEF-Q9 [ejaculatory frequency] and Q10 [orgasmic frequency]). Other measures included IIEF-Intercourse Satisfaction (IS), Overall Satisfaction (OS), and Erectile Function (EF) domains. Changes from baseline to 12 weeks (or last observation) vs. placebo were analyzed using analysis of covariance. Higher IIEF scores indicate better functioning. Of 511 study participants, 310 (60.7%) had ED and were sexually active. The IIEF-OF increased significantly through 12 weeks with tadalafil vs. placebo (P = 0.048), as did IIEF-Q9 (P = 0.045) but not IIEF-Q10 (P = 0.100). Compared with placebo, IIEF-OF, Q9, and Q10 decreased significantly with tamsulosin (all P < 0.05). The IIEF-IS and OS increased significantly at end point with tadalafil (both P < 0.001); for tamsulosin, change was not significant for IS, while OS decreased significantly (P = 0.009). The IIEF-EF domain increased significantly vs. placebo with tadalafil (P < 0.001) but not tamsulosin (P = 0.699). Tadalafil 5 mg once daily significantly improved ejaculation and orgasm, intercourse and overall satisfaction, and erectile function. Men receiving tamsulosin 0.4 mg once daily experienced a decrease in both ejaculatory/orgasmic frequency and overall satisfaction vs. placebo, with no significant effect on erectile function.


Combined theoretical and experimental deep-UV resonance raman studies of substituted pyrenes.
The results of time-dependent density functional theory (TDDFT) calculations of resonance Raman intensities are combined with experimental deep-ultraviolet resonance Raman measurements at a single wavelength, i.e., 244 nm, in order to test the possibility to distinguish several very similar compounds. Pyrene and three of its substituted derivatives, in which a single hydrogen atom has been replaced by a halogen atom, are compared. The fixed 244 nm excitation wavelength overlapped with the same electronic transition of the four pyrenes. Ground-state calculations using the BP86 exchange-correlation functional were used to predict the Raman frequencies, whereas excited-state calculations have been carried out employing the "statistical averaging of (model) orbital potentials" (SAOP) potential within a linear-response TDDFT framework in combination with the short-time approximation of resonance Raman intensities. In view of the simplistic theoretical approach, we find a surprisingly good agreement between the simulated and measured resonance Raman spectra of pyrene and its substituted analogues in terms of frequencies and intensities, which shows that the calculations can be used reliably to interpret the experimental spectra. With this combined information, it is possible to find criteria to distinguish the compounds under investigation, although many features of their vibrational spectra are similar.


Differences in the microstructural properties of the anteromedial and posterolateral bundles of the anterior cruciate ligament.
Tissue properties of the anteromedial (AM) and posterolateral (PL) bundles of the anterior cruciate ligament (ACL) have not been previously characterized with real-time dynamic testing. The current study used a novel polarized light technique to measure the material and microstructural properties of the ACL. The AM and PL bundles of the ACL have similar material and microstructural properties. Controlled laboratory study. The AM and PL bundles were isolated from 16 human cadaveric ACLs (11 male, 5 female; average age, 41 years [range, 24-53 years]). Three samples from each bundle were loaded in uniaxial tension, and a custom-built polarized light imaging camera was used to quantify collagen fiber alignment in real time. A bilinear curve fit was applied to the stress-strain data of a quasistatic ramp-to-failure to quantify the moduli in the toe and linear regions. Fiber alignment was quantified at zero strain, the transition point of the bilinear fit, and in the linear portion of the stress-strain curve by computing the degree of linear polarization (DoLP) and angle of polarization (AoP), which are measures of the strength and direction of collagen alignment, respectively. Data were compared using t tests. The AM bundle exhibited significantly larger toe-region (AM 7.2 MPa vs. PL 4.2 MPa; P < .001) and linear-region moduli (AM 27.0 MPa vs. PL 16.1 MPa; P = .017) compared with the PL bundle. Average DoLP values were similar at low strain but were significantly larger (ie, more uniform alignment) for the AM bundle in the linear region of the stress-strain curve (AM 0.22 vs. PL 0.19; P = .036) compared with the PL bundle. The standard deviation AoP values was larger for the PL bundle at both transition (P = .041) and linear-region strain (P = .014), indicating more disperse orientation. Material and microstructural properties of the AM and PL bundles of the ACL differ during loading. The AM bundle possessed higher tissue modulus and failure stress, as well as more uniform fiber alignment under load. These insights into native ligament microstructure can be used to assess graft options for ACL reconstruction and optimize surgical reconstruction techniques.


Combination of Medical and Surgical Treatments for Masseter Hypertrophy.
Masseter hypertrophy (MH) is one of the uncommon conditions that swelling can be seen in the angular mandibular region of the face. The etiology of MH includes several factors, and various treatment methods are mentioned in the literature. Botulinum toxin type A application is most commonly used for the treatment because of its less invasive feature. As a surgical method, some treatment alternatives that aim to reduce muscle mass or reshape the bone tissue in the angular region are considered. In this case report, a 21-year-old male patient with unilateral masseter hypertrophy on the right side is presented. After the patient was diagnosed with MH, botulinum toxin treatment in two sessions at one-month intervals was done. Since the reduction in muscle volume was not in satisfactory dimensions after the botulinum toxin application, the masseter was reduced on the right side through an intraoral approach. At the same time, bone enlargements on each side of the angulus mandibula were reshaped and smoothened through an extraoral retro mandibular approach. Clinical and radiographic evaluation of the patient revealed more aesthetic and symmetrical appearance in the regular controls.


Substance P activation of rheumatoid synoviocytes: neural pathway in pathogenesis of arthritis.
Several clinical features are consistent with nervous system involvement in the pathogenesis of rheumatoid arthritis. The neuropeptide substance P is one possible mediator of this interaction, since it can be released into joint tissues from primary sensory nerve fibers. The potential effects of the peptide on rheumatoid synoviocytes were examined. The results show that substance P stimulates prostaglandin E2 and collagenase release from synoviocytes. Furthermore, synoviocyte proliferation was increased in the presence of the neuropeptide. Similar effects were observed with a truncated form of substance P. Synoviocytes were sensitive to very small doses of the neuropeptide (10(-9) M), and its effects were inhibited by a specific antagonist. Thus, the specific stimulation of synoviocytes by the neuropeptide substance P represents a pathway by which the nervous system might be directly involved in the pathogenesis of rheumatoid arthritis.


Laser scanning confocal fluorescence microscopy: an overview.
Innovative and important aspects of laser scanning confocal fluorescence imaging (LSCFI) are presented here as a general overview. We have described and discussed the technology of the procedure in some detail. We also report some of our original work with transmembranous uptake of 5S gamma-globulin on living human leukocytes as an example of one specific application of LSCFI. These original data and results are presented, as well as citing other uses and applications, to show the power of LSCFI technique. The article will hopefully be useful for those not familiar with the methodology and utility of laser scanning confocal fluorescence microscopy. Applications of LSCFI are very diverse, and there are new applications of this technology constantly being developed. Interest is growing in LSCFI, particularly in the pharmacologic and therapeutic areas, as demonstrated in this article.


Age-at-Onset and APOE-Related Heterogeneity in Pathologically Confirmed Sporadic Alzheimer Disease.
To characterize age-related clinical heterogeneity in Alzheimer disease (AD) and determine whether it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1,750 patients with sporadic, pathologically confirmed severe AD. In this retrospective cohort study, regression and mixed effects models assessed effects of estimated age at onset, APOE genotype, and their interaction on standardized clinical, cognitive, and pathologic outcome measures from the National Alzheimer's Coordinating Center database. A bimodal distribution of age at onset frequency in APOE ε4- cases showed best separation at age 63. Using this age cutoff, cases were grouped as ε4- early-onset AD (EOAD) (n = 169), ε4+ EOAD (n = 273), ε4- late-onset AD (LOAD) (n = 511), and ε4+ LOAD (n = 797). Patients with EOAD were more likely than patients with LOAD to present with noncognitive behavioral or motor symptoms or nonmemory cognitive complaints, and had more executive dysfunction, but less language impairment on objective cognitive testing. Age at onset and ε4- genotype were independently associated with lower baseline Mini-Mental State Examination scores and greater functional impairment and patients with EOAD had faster cognitive and functional decline than patients with LOAD regardless of APOE genotype. Patients with EOAD were more likely than patients with LOAD to receive a non-AD clinical diagnosis even though they were more likely to have pure AD without concomitant vascular or other non-AD neurodegenerative pathology. Early-onset sporadic AD is associated with a greater likelihood of an atypical, non-memory-dominant clinical presentation, especially in the absence of the APOE ε4 allele, which may lead to misattribution to non-AD underlying pathology.


[Massive myocardial hypertrophy in hypertrophic cardiomyopathy: a risk factor for sudden death and high defibrillation threshold during cardioverter-defibrillator implantation].
Two cases of hypertrophic cardiomyopathy with massive hypertrophy and high defibrillation threshold (DFT) are described. A 14-year-old boy, whose single risk factor for sudden death was extreme hypertrophy with maximum interventricular septum (IVS) thickness of 43 mm, survived an episode of ventricular fibrillation. During ICD implantation DFT testing showed energy requirements >30 J and the procedure was aborted. Amiodarone and verapamil treatment was discontinued and treatment with oral sotalol was instituted. After a period of amiodarone washout the procedure was repeated and DFT of 24 J was encountered. An 18-year-old female with massive hypertrophy (IVS thickness=35 mm) and other risk factors for sudden death underwent ICD implantation for primary prevention. During the procedure DFT=20 J and ICD with 30 J maximal output was implanted. An increase in DFT to more than 20 J was encountered during pre-discharge test. Lack of 10 J safety margin warranted ICD system revision and upgrade; during the second procedure DFT was 24 J and ICD with 35 J maximal output was implanted. In summary, in both cases ICDs with 35 J maximal output were successfully implanted.


Growth characteristics of a herpesvirus of turkeys.
The herpesvirus of turkeys remains associated with cells attached to the culture vessel throughout its growth cycle. The level of infectious centers is essentially constant between 24 and 48 hr when the culture medium is unchanged. Thereafter, the number of infectious centers decreases. The cessation of virus synthesis is not due to insufficient numbers of uninfected cells or interferon production. Herpesvirus of turkeys does not replicate at 22 C and is similar to other herpesviruses in its sensitivity to interferon. The results define conditions to be considered in the preparation of infected cell suspensions commonly used as a vaccine against Marek's disease virus.


Fibrolytic enzyme treatment of barley grain and source of forage in high-grain diets fed to growing cattle.
We conducted a study to determine the effects of treating barley grain with a fibrolytic enzyme mixture on chewing activities, ruminal fermentation, and total tract digestibility in cattle. We also investigated the potential benefits of using barley straw rather than barley silage as a roughage source in high-grain diets for feedlot cattle. Steers were given ad libitum access to one of four diets that consisted of 95% barley-based concentrate and 5% forage (DM basis). The concentrate was either control or enzyme-treated, and the forage was either barley silage or barley straw. Applying the enzyme mixture onto the barley lowered the concentrations of dietary ADF and NDF. However, it is not certain when this fiber hydrolysis occurred relative to feed consumption because the fiber analyses were conducted after the study was completed. Enzyme treatment of barley increased total tract dietary ADF digestibility by 28% (P<.05). Acetate-to-propionate ratio tended to decrease, which suggests that enzymes may have increased ruminal starch digestion as a result of enhanced digestion of barley hulls. Replacing silage with straw increased ADF intake (P<.05) and resulted in 1-h/d increase in rumination time (P<.05). Even though there was no effect of diet on ruminal pH, replacing silage with straw increased ruminal acetate, as a percentage of total VFA, and total tract ADF digestion (P<.01). This study demonstrates that using a fibrolytic enzyme mixture in high-grain diets that contain mainly barley grain can improve fiber digestion and grain utilization, but the mode of action is unclear. Straw can be used rather than silage to increase the effective fiber content of a high-grain feedlot diet.


Primary early thoracoscopy and reduction in length of hospital stay and additional procedures among children with complicated pneumonia: results of a multicenter retrospective cohort study.
To determine the effect of initial procedure type on the length of hospital stay (LOS) and on the requirement for additional pleural fluid drainage procedures in a large multicenter cohort of children with pneumonia complicated by pleural effusion. Retrospective cohort study. Administrative database containing inpatient resource use data from 27 tertiary care children's hospitals. Patients between 12 months and 18 years of age diagnosed as having complicated pneumonia were eligible for the study if they were discharged from the hospital between January 1, 2001, and December 31, 2005, and underwent early (within 2 days of the index hospitalization) pleural fluid drainage. Pleural fluid drainage, categorized as chest tube placement, video-assisted thoracoscopic surgery (VATS), or thoracotomy. The LOS and the requirement for additional pleural fluid drainage. Nine hundred sixty-one of 2862 patients (33.6%) with complicated pneumonia underwent early pleural fluid drainage. Initial procedures included chest tube placement (n = 714), VATS (n = 50), and thoracotomy (n = 197). The median patient age was 4.0 years (interquartile range, 2.0-8.0 years). The median LOS was 10 days (interquartile range, 7-14 days). Two hundred ninety-eight patients (31.0%) required at least 1 additional pleural fluid drainage procedure, and 44 patients (4.6%) required more than 2 pleural fluid drainage procedures. In linear regression analysis, children undergoing primary VATS had a 24% (adjusted beta coefficient, -0.24; 95% confidence interval, -0.41 to -0.07) shorter LOS than patients undergoing primary chest tube placement; this translated into a 2.8-day reduction in the LOS for those undergoing early primary VATS. In logistic regression analysis, patients undergoing primary VATS had an 84% (adjusted odds ratio, 0.16; 95% confidence interval, 0.06-0.42) reduction in the requirement for additional pleural fluid drainage procedures compared with patients undergoing primary chest tube placement. Our large retrospective multicenter study demonstrates that, compared with primary chest tube placement, primary VATS is associated with shorter LOS and fewer additional procedural interventions.


Associations between the age at diagnosis and location of colorectal cancer and the use of alcohol and tobacco: implications for screening.
Individualizing recommendations for colorectal cancer (CRC) screening intervals and modalities requires accurate risk assessment. Although hereditary predisposition is commonly used, the effect of exogenous risk factors has remained largely unexplored. To address this, we analyzed the age at presentation and location of CRC in relation to alcohol and tobacco use. We queried the IMPAC Medical Registry Services Cancer Information Resource File for CRCs diagnosed between June 1, 1993, and December 31, 2003. Subjects were classified as current, past, or never users of alcohol and tobacco. A logistic regression model for location of CRC and a linear regression model for age at diagnosis were constructed using these explanatory variables along with gender, race, and insurance status. Our data set consisted of 161 172 patients with CRC. Current drinking, smoking, and smoking plus drinking were associated with younger ages at onset of CRC (adjusted age difference, 5.2, 5.2, and 7.8 years, respectively; P<.001 for all). A distal location of CRC was more likely to occur in current drinkers (odds ratio, 1.192; 95% confidence interval, 1.15-1.23) and smokers (odds ratio, 1.164; 95% confidence interval, 1.12-1.21). Colorectal cancer in men tended to occur earlier (adjusted age difference, 1.9 years; P<.001) and have a distal predominance (odds ratio, 1.42; P<.001) compared with women. The smoking but not the drinking effect size was greater in women than in men (adjusted age difference, 2.6 years; P<.001). Alcohol use, tobacco use, and male gender were associated with earlier onset and a distal location of CRC. If confirmed, these factors should guide recommendations regarding initiation of CRC screening and, possibly, choice of techniques.


A zero dead-time multi-particle time and position sensitive detector based on correlation between brightness and amplitude.
A new multi-particle time and position sensitive detector using only a set of microchannel plates, a waveform digitizer, a phosphor screen, and a CMOS camera is described. The assignment of the timing information, as taken from the microchannel plates by fast digitizing, to the positions, as recorded by the camera, is based on the COrrelation between the BRightness of the phosphor screen spots, defined as their integrated intensity and the Amplitude of the electrical signals (COBRA). Tests performed by observing the dissociation of HeH, the fragmentation of H3 into two or three fragments, and the photo-double-ionization of Xenon atoms are presented, which illustrate the performances of the COBRA detection scheme.


Extending Goldberg's method to parametrize and control the geometry of Goldberg polyhedra.
Goldberg polyhedra have been widely studied across multiple fields, as their distinctive pattern can lead to many useful applications. Their topology can be determined using Goldberg's method through generating topologically equivalent structures, named cages. However, the geometry of Goldberg polyhedra remains underexplored. This study extends Goldberg's framework to a new method that can systematically determine the topology and effectively control the geometry of Goldberg polyhedra based on the initial shapes of cages. In detail, we first parametrize the cage's geometry under specified topology and polyhedral symmetry; then, we manipulate the predefined independent variables through optimization to achieve the user-defined geometric properties. The benchmark problem of finding equilateral Goldberg polyhedra is solved to demonstrate the effectiveness of the proposed method. Using this method, we have successfully achieved nearly exact spherical Goldberg polyhedra, with all vertices on a sphere and all faces being planar under extremely low numerical errors. Such results serve as strong numerical evidence for the existence of this new type of Goldberg polyhedra. Furthermore, we iteratively perform k-means clustering and optimization to significantly reduce the number of different edge lengths to benefit the cost reduction for architectural and engineering applications.


[Active forces of urinary continence and urethral fatigability. Application to stress urinary incontinence in women].
Eighteen women who had urinary stress incontinence were studied to find the existence of urethral fatigue on effort by using a sphincterometric technique. Urethral pressure measurements at rest as compared with after six heavy coughs showed a mean lowering of the urethral pressure of 40% (range 24.5%-90%) in 10 women. Spectral analysis of the electromyographic trace of the striated urethral sphincter at rest and then after coughing confirms that the striated muscle and the periurethral tissues are involved with a marked quantitative lessening of electric sphincter activity. The clinical, physiopathological, prognostic and therapeutic consequences of this new concept are discussed, together with their relationship to other active forces involved in continence.


Brain Circuits Mediating Opposing Effects on Emotion and Pain.
The amygdala is important for processing emotion, including negative emotion such as anxiety and depression induced by chronic pain. Although remarkable progress has been achieved in recent years on amygdala regulation of both negative (fear) and positive (reward) behavioral responses, our current understanding is still limited regarding how the amygdala processes and integrates these negative and positive emotion responses within the amygdala circuits. In this study with optogenetic stimulation of specific brain circuits, we investigated how amygdala circuits regulate negative and positive emotion behaviors, using pain as an emotional assay in male rats. We report here that activation of the excitatory pathway from the parabrachial nucleus (PBN) that relays peripheral pain signals to the central nucleus of amygdala (CeA) is sufficient to cause behaviors of negative emotion including anxiety, depression, and aversion in normal rats. In strong contrast, activation of the excitatory pathway from basolateral amygdala (BLA) that conveys processed corticolimbic signals to CeA dramatically opposes these behaviors of negative emotion, reducing anxiety and depression, and induces behavior of reward. Surprisingly, activating the PBN-CeA pathway to simulate pain signals does not change pain sensitivity itself, but activating the BLA-CeA pathway inhibits basal and sensitized pain. These findings demonstrate that the pain signal conveyed through the PBN-CeA pathway is sufficient to drive negative emotion and that the corticolimbic signal via the BLA-CeA pathway counteracts the negative emotion, suggesting a top-down brain mechanism for cognitive control of negative emotion under stressful environmental conditions such as pain.SIGNIFICANCE STATEMENT It remains unclear how the amygdala circuits integrate both negative and positive emotional responses and the brain circuits that link peripheral pain to negative emotion are largely unknown. Using optogenetic stimulation, this study shows that the excitatory projection from the parabrachial nucleus to the central nucleus of amygdala (CeA) is sufficient to drive behaviors of negative emotion including anxiety, depression, and aversion in rats. Conversely, activation of the excitatory projection from basolateral amygdala to CeA counteracts each of these behaviors of negative emotion. Thus, this study identifies a brain pathway that mediates pain-driven negative emotion and a brain pathway that counteracts these emotion behaviors in a top-down mechanism for brain control of negative emotion.


In vivo transgene expression from an adenoviral vector is altered following a 6-OHDA lesion of the dopamine system.
We have investigated the in vivo dynamics of an adenovirus-based, LacZ expressing vector, RAd36, at different doses, when injected unilaterally into the corpus striatum of normal rats. We have further investigated the characteristics of this vector in the presence of a 6-OHDA lesion of the nigrostriatal pathway. The dopamine-depleting lesion had an effect on both the number and the distribution of cells transduced by the adenoviral vector. The lesioned side of the brain contained significantly greater numbers of beta-galactosidase positive cells than the unlesioned side at 3 days, 1 week and 4 weeks post-injection and the distribution of transduced cells was altered by the presence of a dopamine lesion. We conclude that the increased levels of transgene expression seen in the lesioned hemisphere are due to a change in the diffusion characteristics of the injected vector in the lesioned hemisphere. These results indicate that, when investigating the use of virus-based vectors, ultimately for use in gene therapies in the CNS, the in vivo dynamics of the vector need to be assessed not only in the normal brain, but also in the pathological brain state such as animal models of target diseases.


Identifying combined design and analysis procedures in two-stage trials with a binary end point.
Two-stage trial designs provide the flexibility to stop early for efficacy or futility and are popular because they have a smaller sample size on average than a traditional trial has with the same type I and II error rates. This makes them financially attractive but also has the ethical benefit of reducing, in the long run, the number of patients who are given ineffective treatments. Designs that minimise the expected sample size are often referred to as 'optimal'. However, two-stage designs can impart a substantial bias into the parameter estimate at the end of the trial. In this paper, we argue that the expected performance of one's chosen estimation method should also be considered when deciding on a two-stage trial design. We review the properties of standard and bias-adjusted maximum likelihood estimators as well as mean and median unbiased estimators. We then identify optimal two-stage design and analysis procedures that balance projected sample size considerations with those of estimator performance. We make available software to implement this new methodology.


Imaging Brain Mechanisms of Functional Somatic Syndromes: Potential as a Biomarker?
When patients present with persistent bodily complaints that cannot be explained by a symptom-linked organic pathology (medically unexplained symptoms), they are diagnosed with 'functional' somatic syndromes (FSS). Despite their prevalence, the management of FSS is notoriously challenging in clinical practice. This may be because FSS are heterogeneous disorders in terms of etiopathogenesis. They include patients with primarily peripheral dysfunction, primarily centrally driven somatic symptoms, and a mix of both. Brain-imaging studies, particularly data-driven pattern recognition methods using machine learning algorithms, could provide brain-based biomarkers for these clinical conditions. In this review, we provide an overview of our brain imaging data on brain-body interactions in one of the most well-known FSS, irritable bowel syndrome (IBS), and discuss the possible development of a brain-based biomarker for FSS. Anticipation of unpredictable pain, which commonly elicits fear in FSS patients, induced increased activity in brain areas associated with hypervigilance during rectal distention and non-distention conditions in IBS. This was coupled with dysfunctional inhibitory influence of the medial prefrontal cortex (mPFC) and pregenual anterior cingulate cortex (pACC) on stress regulation systems, resulting in the activated autonomic nervous system (ANS) and neuroendocrine system stimulated by corticotropin-releasing hormone (CRH). IBS subjects with higher alexithymia, a risk factor for FSS, showed stronger activity in the insula during rectal distention but reduced subjective sensitivity. Reduced top-down regulation of the ANS and CRH system by mPFC and pACC, discordance between the insula response to stimulation and subjective sensation of pain, and stronger threat responses in hypervigilance-related areas may be a candidate brain-based biomarker.


Management of Endometriosis: Toward Value-Based, Cost-Effective, Affordable Care.
Endometriosis management seems to be influenced by outcome-independent biomedical, pharmacological, and technological developments. The propensity towards doing more affects several aspects of care, sometimes translating into proposals that are not based on sound epidemiological principles and robust evidence. Different stakeholders share the interest for doing more testing and using novel and costly drugs or devices in patients with endometriosis. Although some women may benefit from such an approach, the majority do not, and some may be harmed. Moreover, an uncontrolled increase in expenditures for endometriosis management without demonstrated and proportional health benefits would waste the finite resources of national health care services and would risk cost-related non-adherence. Cost-effectiveness analyses should be systematically pre-planned in future trials on endometriosis, and the concept of "value" of medical interventions should guide investigators and health care policymakers. Reducing low-value care, financial toxicity, and the burden of treatment is respectful not only of endometriosis patients, but also of the entire society. Whenever possible, long-term therapeutic strategies should be tailored to each woman's needs, and high-value tests and treatments should be chosen based on her priorities and preferences. Moreover, listening to patients, understanding their concerns, avoiding disease labelling, explaining plainly what is known and what is unknown, and giving constant reassurance and encouragement may be exceedingly important for the successful management of endometriosis and may change the patient's perception of her clinical condition. Physician empathy has no untoward effects, does not cause harms, and may determine whether a woman successfully copes or desperately struggles with her disease during reproductive life.


Learning curves in manufacturing.
Large increases in productivity are typically realized as organizations gain experience in production. These "learning curves" have been found in many organizations. Organizations vary considerably in the rates at which they learn. Some organizations show remarkable productivity gains, whereas others show little or no learning. Reasons for the variation observed in organizational learning curves include organizational "forgetting," employee turnover, transfer of knowledge from other products and other organizations, and economies of scale.


Extrahepatic biliary atresia with cartilaginous metaplasia in the gallbladder remnants.
Extrahepatic biliary atresia (EBA) is a chronic inflammatory process leading to fibrous obliteration of the biliary tree. Cartilaginous metaplasia within the remaining walls of the biliary main ducts in EBA has been reported once, although as cartilage heterotopia. A similar finding is presented here, but in the gallbladder of an infant with the full-blown manifestations of EBA; it is proposed that the alteration results from metaplasia of local connective tissue. Also of note is the complete disappearance of smooth muscle cells in the walls of the biliary tree in EBA, a fact which seems to be missing in the description of the pathology in these cases.


Selective photocatalytic production of CH4 using Zn-based polyoxometalate as a nonconventional CO2 reduction catalyst.
Efficient and selective production of CH4 through the CO2 reduction reaction (CO2RR) is a challenging task due to the high amount of energy consumption and various reaction pathways. Here, we report the synthesis of Zn-based polyoxometalate (ZnPOM) and its application in the photocatalytic CO2RR. Unlike conventional Zn-based catalysts that produce CO, ZnPOM can selectively catalyze the production of CH4 in the presence of an Ir-based photosensitizer (TIr3) through the photocatalytic CO2RR. Photophysical and computation analyses suggest that selective photocatalytic production of CH4 using ZnPOM and TIr3 can be attributed to (1) the exceptionally fast transfer of photogenerated electrons from TIr3 to ZnPOM through the strong molecular interactions between them and (2) effective transfer of electrons from ZnPOM to *CO intermediates due to significant hybridization of their molecular orbitals. This study provides insights into the design of novel CO2RR catalysts for CH4 production beyond the limitations in conventional studies that focus on Cu-based materials.


Stable isotopes reveal winter feeding in different habitats in blue, fin and sei whales migrating through the Azores.
Knowing the migratory movements and behaviour of baleen whales is fundamental to understanding their ecology. We compared δ15N and δ13C values in the skin of blue (Balaenoptera musculus), fin (Balaenoptera physalus) and sei (Balaenoptera borealis) whales sighted in the Azores in spring with the values of potential prey from different regions within the North Atlantic using Bayesian mixing models to investigate their trophic ecology and migration patterns. Fin whale δ15N values were higher than those recorded in blue and sei whales, reflecting feeding at higher trophic levels. Whales' skin δ15N and δ13C values did not reflect prey from high-latitude summer foraging grounds; instead mixing models identified tropical or subtropical regions as the most likely feeding areas for all species during winter and spring. Yet, differences in δ13C values among whale species suggest use of different regions within this range. Blue and sei whales primarily used resources from the Northwest African upwelling and pelagic tropical/subtropical regions, while fin whales fed off Iberia. However, determining feeding habitats from stable isotope values remains difficult. In conclusion, winter feeding appears common among North Atlantic blue, fin and sei whales, and may play a crucial role in determining their winter distribution. A better understanding of winter feeding behaviour is therefore fundamental for the effective conservation of these species.


Accelerated Black-Blood Cine MR Imaging with Low-Rank and Sparsity Constraints.
Black-blood MRI is a promising imaging technique for assessing vascular diseases (e.g., stroke). Vessel wall dynamic characterization using black-blood cine MRI has been recognized as an effective tool for studying vascular diseases. However, acquiring time-resolved 3D vessel wall images often requires a long acquisition time, which limits its clinical utility. In this work, we develop a new method to achieve rapid, time-resolved 3D black-blood cine MRI. Specifically, the proposed method performs (k, t)-space undersampling to accelerate the volumetric data acquisition process. Moreover, it utilizes an image reconstruction method with low-rank and sparsity constraints to enable high-quality image reconstruction from highly-undersampled data. We validate the performance of the proposed method with 3D in vivo black-blood cine MRI experiments and show representative results to demonstrate the utility of the proposed method.


The effects of a novel hormonal breast cancer therapy, endoxifen, on the mouse skeleton.
Endoxifen has recently been identified as the predominant active metabolite of tamoxifen and is currently being developed as a novel hormonal therapy for the treatment of endocrine sensitive breast cancer. Based on past studies in breast cancer cells and model systems, endoxifen classically functions as an anti-estrogenic compound. Since estrogen and estrogen receptors play critical roles in mediating bone homeostasis, and endoxifen is currently being implemented as a novel breast cancer therapy, we sought to comprehensively characterize the in vivo effects of endoxifen on the mouse skeleton. Two month old ovariectomized C57BL/6 mice were treated with vehicle or 50 mg/kg/day endoxifen hydrochloride via oral gavage for 45 days. Animals were analyzed by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, micro-computed tomography and histomorphometry. Serum from control and endoxifen treated mice was evaluated for bone resorption and bone formation markers. Gene expression changes were monitored in osteoblasts, osteoclasts and the cortical shells of long bones from endoxifen treated mice and in a human fetal osteoblast cell line. Endoxifen treatment led to significantly higher bone mineral density and bone mineral content throughout the skeleton relative to control animals. Endoxifen treatment also resulted in increased numbers of osteoblasts and osteoclasts per tissue area, which was corroborated by increased serum levels of bone formation and resorption markers. Finally, endoxifen induced the expression of osteoblast, osteoclast and osteocyte marker genes. These studies are the first to examine the in vivo and in vitro impacts of endoxifen on bone and our results demonstrate that endoxifen increases cancellous as well as cortical bone mass in ovariectomized mice, effects that may have implications for postmenopausal breast cancer patients.


Psychotic Like Experiences are Associated with Suicide Ideation and Behavior in 9 to 10 Year Old Children in the United States.
Those experiencing psychotic like experiences (PLEs) are at higher risk for suicide ideation and behavior. However, it is unclear if PLEs are related to suicide ideation and behavior in children, and whether other factors such as impulsivity or emotion dysregulation might moderate the relationship. We hypothesize that PLEs are associated with suicide ideation and behavior, with impulsivity and emotion dysregulation moderating this relationship, in middle childhood. History of PLEs, suicide ideation and behavior, depression, emotion dysregulation, and impulsivity were assessed for 10,624 children aged 9 to 10.9 years (47.8% female, 34.4% minority race, 20.0% Hispanic) as part of the Adolescent Brain Cognitive Development℠ study. Hypotheses about associations between variables were assessed using hierarchical linear modeling. PLEs were associated with suicide ideation and suicide behavior even when controlling for depression severity. Emotion dysregulation and impulsivity were also associated with suicide ideation and moderated the relationship between PLEs and suicide ideation. Variation in suicide ideation due to impulsivity and emotion dysregulation appears to be strongest when people are experiencing low levels to no PLEs. Only impulsivity and PLEs were associated with suicide behavior. Depression was associated with suicide ideation, but not suicide behavior. PLEs may be an important risk factor for suicide ideation and behavior in 9 to 10-year-old children, comparable to adult and adolescent populations. When considering prevention of suicidality, these data suggest that considering the relations between PLEs, impulsivity and emotion dysregulation may be important.


Ras p21 as a potential mediator of insulin action in Xenopus oocytes.
The oncogene protein product (p21) of the ras gene has been implicated in mediating the effects of a variety of growth factors and hormones. Microinjection of monoclonal antibody 6B7, which is directed against a synthetic peptide corresponding to a highly conserved region of p21 (amino acids 29 to 44) required for p21 function, specifically inhibited Xenopus oocyte maturation induced by incubation with insulin. The inhibition was dose-dependent and specific since (i) the same antibody had no effect on progesterone-induced maturation, (ii) immunoprecipitation and Western blotting indicated that the antibody recognized a single protein of molecular weight 21,000 in oocyte extracts, and (iii) inhibition was not observed with identical concentrations of normal immunoglobulin. Thus, p21 appears to be involved in mediating insulin-induced maturation of Xenopus oocytes. Furthermore, the mechanism may involve phosphorylation of p21, as p21 was found to be a substrate of the insulin receptor kinase.


Dietary intake and blood lipid profile survey of fighter pilots at Tyndall Air Force Base.
A 24-hour dietary recall, a food frequency checklist, and a blood lipid profile were collected from 30 USAF fighter pilots. Sample mean intakes of nutrients studied met U.S. military recommended dietary allowances, except for folic acid, which was 78%. Mean percentages of energy derived from carbohydrate, protein and fat were 48.3, 16.1 and 34.2%, respectively. Of the pilot sample, 63% reported they did not eat breakfast daily. Sample mean blood lipid profile values were: total cholesterol = 218 mg/dl, HDL-cholesterol = 45 mg/dl, triglycerides = 109 mg/dl. Based on total cholesterol level, 40% of the pilot sample should have follow-up according to the National Cholesterol Education Program. A significant negative relationship was found between reported exercise frequency and total cholesterol/HDL-cholesterol ratio. Some fighter pilots could benefit from counseling with a dietitian regarding dietary intake patterns, decreasing dietary fats, and the advantages of regular exercise.


Impact of spleen-preserving total gastrectomy on postoperative infectious complications and 5-year overall survival: systematic review and meta-analysis of contemporary randomized clinical trials.
The role of splenectomy in proximal gastric cancer is still debated. The objective of the present meta-analysis was to provide more-robust evidence about the effect of spleen-preserving total gastrectomy on postoperative infectious complications, overall morbidity, and 5-year overall survival (os). PubMed, embase, and the Web of Science were consulted. Pooled effect measures were calculated using an inverse-variance weighted or Mantel-Haenszel in random effects meta-analysis. Heterogeneity was evaluated using I2 index and Cochran Q-test. Three randomized controlled trials published between 2000 and 2018 were included. Overall, 451 patients (50.1%) underwent open total gastrectomy with spleen preservation and 448 (49.9%) underwent open total gastrectomy with splenectomy. The patients ranged in age from 24 to 78 years. No differences were found in the number of harvested lymph nodes (p = 0.317), the reoperation rate (p = 0.871), or hospital length of stay (p = 0.347). The estimated pooled risk ratios for infectious complications, overall morbidity, and mortality were 1.53 [95% confidence interval (ci): 1.09 to 2.14; p = 0.016], 1.51 (95% ci: 1.11 to 2.05; p = 0.008), and 1.23 (95% ci: 0.40 to 3.71; p = 0.719) respectively. The estimated pooled hazard ratio for 5-year os was 1.06 (95% ci: 0.78 to 1.45; p = 0.707). Spleen-preserving total gastrectomy should be considered in patients with curable gastric cancer because it is significantly associated with decreased postoperative infectious complications and overall morbidity, with no difference in the 5-year os. Those observations appear worthwhile for establishing better evidence-based treatment for gastric cancer.


Bulboventricular foramen resection: hemodynamic and electrophysiologic results.
The two major surgical approaches to the relief of bulboventricular foramen (BVF) obstruction in patients with single left ventricle (LV) are the Damus-Kaye-Stansel (DKS) procedure or direct BVF resection. Theoretical advantages of the DKS include better out-flow gradient relief, lower potential incidences of postoperative heart block and lower incidences of reoperation. Potential disadvantages of this approach include increased semilunar valvar insufficiency, lack of feasibility when attempting septation-type operations for univentricular hearts, and a technically more difficult operation. We report the results of direct surgical BVF resection. From June 1990 to June 1999, 9 patients had direct BVF resection performed at our institution. The median age at surgery was 16.5 years (range 1 month to 27 years). Diagnoses in these patients were [S,L,L] single LV (n = 8) and [S,D,D] single LV tricuspid atresia (n = 1). Eight of 9 patients had pulmonary artery bands placed either before BVF resection or at the same time as this procedure. Three patients required reoperation for reobstruction at the BVF (12 total operations in 9 patients). Median preoperative peak systolic gradient across the BVF measured at cardiac catheterization was 47 mm Hg (range 10 to 63 mm Hg). The median peak gradient measured by Doppler echocardiography was 44 mm Hg (range 5 to 125 mm Hg). Eight of 9 patients survived the operation to discharge from the hospital and 7 of 9 are alive at follow-up. At a median follow-up of 22 months (range 5 to 76 months), 8 of 8 surviving patients had an unobstructed BVF as determined by qualitative two-dimensional echocardiography and Doppler color flow imaging. There was one perioperative and one late death 5 months postoperatively (secondary to fungal sepsis). No patient developed new or worsened aortic insufficiency after BVF resection. Eight of 9 patients had no change in AV nodal conduction after surgery. One patient developed Mobitz II heart block requiring postoperative implantation of a pacemaker. Direct resection of an obstructive BVF can be performed with total relief of obstruction although reoperation may be required. Atrioventricular nodal function can be preserved in most patients with this operative approach, including those with [S,L,L] segmental anatomy.


Molecular mechanisms of β-lactam resistance in carbapenemase-producing Klebsiella pneumoniae from Sri Lanka.
Carbapenemases are increasingly important antimicrobial resistance determinants. Little is known about the carbapenem resistance mechanisms in Sri Lanka. We examined 22 carbapenem-resistant Klebsiella pneumoniae from Sri Lanka to determine their β-lactam resistance mechanisms. The predominant resistance mechanisms we detected in this study were OXA-181, NDM-1 carbapenemases and extended-spectrum β-lactamase CTX-M-15. All isolates were then genotyped by pulsed-field gel electrophoresis, variable-number tandem repeat sequence analysis and multilocus sequence typing, and seven distinct genotypes were observed. Five OXA-181-positive Klebsiella pneumoniae isolates were genotypically related to an isolate of Indian origin. Multilocus sequence typing found that these related isolates belong to ST-14, which has been associated with dissemination of OXA-181 from the Indian subcontinent. Other genotypes we discovered were ST-147 and ST-340, also associated with intercontinental spread of carbapenemases of suspected subcontinental origin. The major porin genes ompK35 and ompK36 from these isolates had insertions, deletions and substitutions. Some of these were exclusive to strains within single pulsotypes. We detected one ompK36 variant, ins AA134-135GD, in six ST-14- and six ST-147, blaOXA-181-positive isolates. This porin mutation was an independent predictor of high-level meropenem resistance in our entire Sri Lankan isolate collection (P=0.0030). Analysis of the Sri Lankan ST-14 and ST-147 ins AA134-135GD-positive isolates found ST-14 was more resistant to meropenem than other isolates (mean MIC: 32±0 µg ml(-1) and 20±9.47 µg ml(-1), respectively, P=0.0277). The likely international transmission of these carbapenem resistance determinants highlights the need for regional collaboration and prospective surveillance of carbapenem-resistant Enterobacteriaceae.


What is new in the treatment of multiple sclerosis?
Multiple sclerosis (MS) is considered an autoimmune disease associated with immune activity directed against central nervous system antigens. Based on this concept, immunosuppression and immunomodualtion have been the mainstays of therapeutic strategies in MS. During the last decade new therapies have been shown to significantly improve MS disease course. The effective therapies have led to a better understanding of MS pathogenesis and further development of even more efficient therapeutic interventions. Recombinant interferon (IFN)beta represents the first breakthrough in MS therapy. Three large placebo-controlled, double-blind studies and several smaller studies have demonstrated the efficacy of different forms of IFNbeta administrated by either subcutaneous or intramuscular routes and at different doses in patients with active relapsing-remitting multiple sclerosis (RR-MS). The three IFNbeta drugs are IFNbeta-1b and two IFNbeta-1a preparations (Avonex and Rebif). Although each clinical trial had unique features and differences that make direct comparisons difficult, the aggregate results demonstrate a clear benefit of IFNbeta for decreasing relapses and probability of sustained clinical disability progression in patients with RR-MS. All forms of IFNbeta therapy had beneficial effects on the disease process measured by brain magnetic resonance imaging (MRI). IFNbeta-1a (Avonex) also showed benefit in slowing or preventing the development of MS related brain atrophy measured by MRI after 2 years of therapy. Glatiramer acetate, the acetate salt of a mixture synthetic polypeptides thought to mimic the myelin basic protein showed a significant positive results in reducing the relapse rate in patients with RR-MS. Follow up of these patients for approximately 3 years continued to show a beneficial effect on disease relapse rate. Recent MRI data supported the beneficial clinical results seen with glatiramer acetate in patients with RR-MS. Recent studies using intravenous immune globulin (IVIG) suggest that IVIG could be effective to some degree in patients with RR-MS. However, there is not enough evidence that IVIG is equivalent to IFNbeta or glatiramer acetate in the treatment of patients with RR-MS. There have also been recent therapeutical advances in secondary progressive MS (SP-MS). A recent large phase II, placebo-controlled study with IFNbeta-1b in patients with SP-MS convincingly documented that IFNbeta-1b slowed progression of the disease independent of the degree of the clinical disability at the time of treatment initiation and independent of presence of superimposed relapses. Mitoxantrone, an anthracenedione synthetic agent, was also shown to be effective as treatment for active SP-MS. It is well tolerated but the duration of treatment is limited by cumulative cardiotoxicity. There is a growing consensus that disease-modifying therapies should be initiated early in the course of the disease before irreversible clinical disability has developed. Different therapies should be considered and tailored based on patient condition. Combination therapies could be considered as a therapeutic option for patients that failed therapies with IFNbeta and/or glatiramer acetate. Currently, there are new ongoing studies testing safety and/or efficacy of different combination regimens (i.e. azathioprine with IFNbeta, IFNbeta with glatiramer acetate, or pulses of intravenous cyclophosphamide with IFNbeta). Determining the effect of different therapies on the course of the disease within large clinical studies appears easier than determining individual responsiveness. Therefore, standardised methods for evaluating individual patients receiving disease-modifying therapies and development of effective therapeutic algorithms are needed.


Longitudinal profiles of expressive vocabulary, syntax and pragmatic language in boys with fragile X syndrome or Down syndrome.
Fragile X syndrome (FXS) and Down syndrome (DS) are the two leading genetic causes of intellectual disability, and FXS is the most common known genetic condition associated with autism. Both FXS and DS are associated with significant language impairment, but little is known about expressive language across domains over time or the role of autism in language development in FXS. To compare three domains of language production (vocabulary, syntax, pragmatics) over time within and across groups of boys with FXS with and without autism spectrum disorder (FXS-ASD, FXS-O), boys with DS, and typically developing (TD) boys. Twenty-nine boys with FXS-O, 40 boys with FXS-ASD, 34 boys with DS, and 48 younger TD boys of similar non-verbal mental age living in the United States participated in the study. The Antonyms, Syntax Construction and Pragmatic Judgment subtests of the Comprehensive Assessment of Spoken Language were administered annually over 3 years. TD boys scored higher than all other groups on all three subtests; boys with FXS-O and FXS-ASD scored higher than boys with DS in Syntax Construction; and boys with FXS-O scored higher than boys with FXS-ASD in Pragmatic Judgment. Within-group patterns varied between groups. Overall, the TD group showed significantly more change over time than all other groups. Findings suggest that expressive language skills and growth across various domains are more impaired in boys with FXS and DS than would be expected based on non-verbal mental age, that for boys with DS syntax is more impaired than would be expected based on intellectual disability, and that autism status affects pragmatic language in boys with FXS. Findings suggest that language production across domains should be addressed during assessment and intervention for boys with FXS and boys with DS, with differing group profiles also suggesting potentially different areas of focus.


Multifunctionality of Additively Manufactured Kelvin Foam for Electromagnetic Wave Absorption and Load Bearing.
Rationally engineered porous structures enable lightweight broadband electromagnetic (EM) wave absorbers for countering radar signals or mitigating EM interference between multiple components. However, the scalability of such structures has been hindered by their limited mechanical properties resulting from low density. Herein, an additively manufactured Kelvin foam-based EM wave absorber (KF-EMA) is reported that exhibits multifunctionality, namely EM wave absorption and light-weighted load-bearing structures with constant relative stiffness made possible using bending-dominated lattice structures. Based on tuning design parameters, such as the backbone structures and constituent materials, the proposed KF-EMA features a multilayered 3D-printed design with geometrically optimized KF structures made of carbon black-based backbone composites. The developed KF-EMA demonstrated an absorbance greater than 90% at frequencies ranging from 5.8 to 18 GHz (average EM wave absorption rates of 95.89% and maximum of 99.1% at 15.8 GHz), while the low-density structures of the absorber (≈200 kg m-3 ) still maintained a compression index between the stiffness and relative density (n = 2) under compression. The design strategy paves the way for using metamaterials as mechanically reinforced EM wave absorbers that enable multifunctionality by optimizing unit-cell parameters through a single and low-density structure.